Neonatal (or perinatal) asphyxia, also known as hypoxia-ischemia (HI), is a condition arising from the inadequate intake of oxygen in an infant during labour, delivery, or the immediate postnatal period. Neonatal asphyxia remains a major cause of chronic neurological morbidity and acute mortality in the newborn (Balduini et al, 2000; Vannucci et al, 1997) and commonly leads to hypoxic-ischemic encephalopathy.
Studies have shown that neonatal asphyxia (hypoxia) for as short a time as six minutes can lead to permanent neurological damage. Loss of brain tissue has been demonstrated in asphyxiated newborn primates and correlated with memory dysfunction and spastic paralysis (Windle, WF, 1969).
About 14.6% of all deaths at birth are caused by neonatal asphyxia. In the western world about 0.9% (i.e. 100-130,000) of newborns suffer from neonatal asphyxia. About 15-20% die, and of the survivors, 25% are severely handicapped due to long-term complications such as mental retardation, cerebral palsy, spasticity, learning difficulties and/or epilepsy (Law et al, 1993; Perlman et al. 1999). Furthermore, it is increasingly recognized that children with rather mild asphyxia, who seem initially to recover without complications, have behavioral problems in childhood, which can be traced back to this neonatal insult. Neonatal asphyxia meets the criteria for an orphan drug indication since it affects less then 5 patients in 10,000 inhabitants, and is a life-threatening, serious debilitating disease without an established therapy.
It has been demonstrated in neonatal animal models of HI that the mechanisms of cell death involved in this type of brain injury, involve a combination of excitotoxic damage (or necrosis), caused by excessive activation of glutamate receptors, particularly N-methyl-D-aspartate (NMDA) receptors, as they are most sensitive to neurotoxicity during periods of synaptogenesis (Jevtovic-Todorovic and Olney, 2003), and by apoptotic neurodegeneration (Ikonomidou et al, 1989; Pohl et al, 1999). The type of damage is related to the severity of the hypoxic insult (Jevtovic-Todorovic and Olney, 2003) and also to the variation in vulnerability of the different brain regions (Northington et al, 2001). Currently, no effective therapy exists to combat the acute neuronal cell death caused by HI, although a variety of both pharmacological and non-pharmacological interventions are under experimental investigation (Vannucci and Perlman, 1997).
The present invention seeks to provide a method of treating neonatal asphyxia.